Carotenoid ester analogs or derivatives for controlling connexin 43 expression

Abstract

A method of controlling (e.g., influencing or affecting) connexin 43 expression in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation. In some embodiments, controlling connexin 43 expression in a subject may effectively treat cardiac arrhythmia and/or cancerous and pre-cancerous cells in a subject. The pharmaceutically acceptable formulation may include a synthetic analog or derivative of a carotenoid. The subject may be administered a carotenoid analog or derivative, either alone or in combination with another carotenoid analog or derivative, or co-antioxidant formulation. The carotenoid analog may include a conjugated polyene with between 7 to 14 double bonds. The conjugated polyene may include a cyclic ring including at least one substituent. In some embodiments, a cyclic ring of a carotenoid analog or derivative may include at least one substituent. The substituent may be coupled to the cyclic ring with an ester functionality.

1 - 2022 . (cancelled)  
     
     
         2023 . A method of controlling connexin 43 expression in a subject comprising administering to the subject an effective amount of a pharmaceutically acceptable formulation comprising a synthetic carotenoid analog or derivative; 
 wherein the synthetic analog or derivative of the carotenoid has the structure:                          where z is from 5 to 12;    where each R 3  is independently hydrogen or methyl;    where each Y is independently O or H 2 ;    where each R is independently OR 1  or R 1 ;    where each R 1  is independently-alkyl-NR 2   3   + , -aromatic-NR 2   3   + , -alkyl-CO 2   − , -aromatic-CO 2   − , -amino acid-NH 3   + , -phosphorylated amino acid-NH 3   + , polyethylene glycol, dextran, H, alkyl, or aryl; and    where each R 2  is independently H, alkyl, or aryl.    
     
     
         2024 . The method of  claim 2023 , wherein the carotenoid analog or derivative is at least partially water soluble.  
     
     
         2025 . The method of  claim 2023 , wherein Y is H 2 , and wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2026 . The method of  claim 2023 , wherein Y is O, and wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2027 . The method of  claim 2023 , wherein the carotenoid analog or derivative further comprises at least one chiral center.  
     
     
         2028 . The method of  claim 2023 , wherein the carotenoid analog or derivative is a analog or derivative of a naturally occurring carotenoid.  
     
     
         2029 . The method of  claim 2023 , wherein the carotenoid analog or derivative is a analog or derivative of a naturally occurring carotenoid, and wherein the naturally occurring carotenoid is astaxanthin, beta-carotene, lutein, zeaxanthin, or canthaxanthin.  
     
     
         2030 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
         where each X is independently -alkyl-NR 4   3   + , -aromatic-NR 4   3   + , -alkyl-CO 2   − , -aromatic-CO 2   − , -amino acid-NH 3   + , -phosphorylated amino acid-NH 3   + , polyethylene glycol, dextran, H, alkyl, or aryl, and where each R 4  is independently H, alkyl, or aryl;  
         where each R′ is independently -alkyl-O, alkyl, or aryl; and  
         where n is between 0 and about 12.  
       
     
     
         2031 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
         where each X is independently -alkyl-NR 4   3   + , -aromatic-NR 4   3   + , -alkyl-CO 2   − , -aromatic-CO 2   − , -amino acid-NH 3   + , -phosphorylated amino acid-NH 3   + , polyethylene glycol, dextran, H, alkyl, or aryl, and where each R 4  is independently H, alkyl, or aryl;  
         where each R′ is independently -alkyl-O, alkyl, or aryl; and  
         where n is between 0 and 12.  
       
     
     
         2032 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2033 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2034 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2035 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2036 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2037 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2038 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2039 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2040 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2041 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2042 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2043 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2044 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2045 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2046 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2047 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2048 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2049 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2050 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2051 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2052 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2053 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2054 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2055 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2056 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2057 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2058 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2059 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2060 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2061 . The method of  claim 2023 , wherein the carotenoid analog or derivative has the structure  
       
         
           
           
               
               
           
         
       
     
     
         2062 . The method of  claim 2023 , wherein the carotenoid analog or derivative is at least partially water dispersible.  
     
     
         2063 . The method of  claim 2023 , wherein each R 1  is independently  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2064 . The method of  claim 2023 , wherein the subject is a mammal.  
     
     
         2065 . The method of  claim 2023 , wherein the subject is human.  
     
     
         2066 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises administering the pharmaceutically acceptable formulation to a subject parenterally.  
     
     
         2067 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises administering the carotenoid analog or derivative to a subject parenterally at a dose of about 5 mg to about 300 mg per day.  
     
     
         2068 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises administering the carotenoid analog or derivative to a subject parenterally at a dose of about 0.25 mg to about 1.0 g per day.  
     
     
         2069 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises intracoronary administration of the pharmaceutically acceptable formulation to a subject.  
     
     
         2070 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises intracoronary administration of the carotenoid analog or derivative to a subject at a dose of about 5 mg to about 300 mg per day.  
     
     
         2071 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises intracoronary administration of the carotenoid analog or derivative to a subject at a dose of about 0.25 mg to about 1.0 g per day.  
     
     
         2072 . The method of  claim 2023 , wherein administering pharmaceutically acceptable formulation to a subject comprises administering the pharmaceutically acceptable formulation to a subject subcutaneously.  
     
     
         2073 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises administering the carotenoid analog or derivative to a subject orally.  
     
     
         2074 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises administering the carotenoid analog or derivative to a subject orally at a dose of about 5 mg to about 100 mg per day.  
     
     
         2075 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises administering the carotenoid analog or derivative to a subject orally at a dose of about 0.25 mg to about 1.0 g per day.  
     
     
         2076 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises administering the carotenoid analog or derivative at a dose in a range of about 0.25 mg to about 1 g.  
     
     
         2077 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises administering at least two different carotenoid analog or derivatives.  
     
     
         2078 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation reduces the numberof cancerous and pre-cancerous cells.  
     
     
         2079 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation reduces the numberof cancerous cells, wherein cancerous cells comprise carcinogen-initiated cell.  
     
     
         2080 . The method of  claim 2023 , further comprising controlling intercellular gap junctional communication.  
     
     
         2081 . The method of  claim 2023 , further comprising treating cardiac arrhythmia.  
     
     
         2082 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises administering the carotenoid analog or derivative to a subject in the form of an emulsion.  
     
     
         2083 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises administering the pharmaceutically acceptable formulation to a subject in the form of an emulsion comprising water, oil and lecithin.  
     
     
         2084 . The method of  claim 2023 , wherein administering the pharmaceutically acceptable formulation to a subject comprises a direct relationship between the amount of the carotenoid analog or derivative administered and an effect of the administered carotenoid analog or derivative.  
     
     
         2085 . The method of  claim 2023 , further comprising inhibiting at least some of the substantially negative consequences of a disease state.  
     
     
         2086 . The method of  claim 2023 , further comprising reducing at least some of the substantially negative consequences of a disease state.  
     
     
         2087 . The method of  claim 2023 , wherein the carotenoid analog or derivative may decompose during use, wherein one or more of the products of the decomposition may be more biologically active relative to the carotenoid analog or derivative.  
     
     
         2088 . The method of  claim 2023 , further comprising administering a co-antioxidant.  
     
     
         2089 . A method of treating cardiac arrhythmia in a subject comprising administering to the subject an effective amount of a pharmaceutically acceptable formulation comprising a synthetic carotenoid analog or derivative; 
 wherein the synthetic analog or derivative of the carotenoid has the structure:                          where z is from 5 to 12;    where each R 3  is independently hydrogen or methyl;    where each Y is independently O or H 2 ;    where each R is independently OR 1  or R 1 ;    where each R 1  is independently -alkyl-NR 2   3   + , -aromatic-NR 2   3   + , -alkyl-CO 2   − , -aromatic-CO 2   − , -amino acid-NH 3   + , -phosphorylated amino acid-NH 3   + , polyethylene glycol, dextran, H, alkyl, or aryl; and    where each R 2  is independently H, alkyl, or aryl.    
     
     
         2090 - 2153 . (cancelled)  
     
     
         2154 . A method of treating cancerous and pre-cancerous cells in a subject comprising administering to the subject an effective amount of a pharmaceutically acceptable formulation comprising a synthetic carotenoid analog or derivative; 
 Wherein the synthetic analog or derivative of the carotenoid has the structure:                          where z is from 5 to 12;    where each R 3  is independently hydrogen or methyl;    where each Y is independently O or H 2 ;    where each R is independently OR 1  or R 1 ;    where each R 1  is independently -alkyl-NR 2   3   + , -aromatic-NR 2   3   + , -alkyl-CO 2   − , -aromatic-CO 2   − , -amino acid-NH 3   + , -phosphorylated amino acid-NH 3   + , polyethylene glycol, dextran, H, alkyl, or aryl; and    where each R 2  is independently H, alkyl, or aryl.    
     
     
         2155 - 2529 . (cancelled)